Sex influences the clinical manifestations of many human diseases. Sex may affect prevalence, severity, or even specific clinical manifestations. At present, specific mechanisms responsible for these sex differences in so many different diseases are not well understood. One reason for the limited understanding is that the types of experimental manipulations most helpful for definitively delineating the responsible mechanisms cannot be conducted in affected human populations. In this setting, animal models can be valuable for preliminary identification of mechanisms that subsequently can be verified in humans. We recently identified a novel animal model useful for dissecting sex contributions in neurological disease. Rocker mice carry a mutation in Cacna1a, an autosomal gene that encodes a key subunit of the CaV2.1 voltage-regulated calcium channel. In humans different mutations in the same gene are responsible for a variety of neurological disorders including episodic ataxia, familial hemiplegic migraine, spinocerebellar ataxia 6, epilepsy, benign paroxysmal torticollis of infancy, and focal or segmental dystonias. In humans, several such disorders demonstrate sex differences in expression. In the rocker mutants, transient attacks of disabling motor dysfunction resembling human paroxysmal dystonia occur frequently in female rockers, but are absent in males. Ovariectomy eliminates attacks in females, suggesting an ovarian influence. The goal of the current project is to begin to dissect the hormonal influences that could be responsible for the sex differences in these mice. Aim 1 addresses the potential role of estrogen and/or progesterone supplements in restoring attacks in ovariectomized females. Aim 2 addresses the relationship between attacks and the hormonal changes of pregnancy. Aim 3 addressed the potential ability of female sex steroid hormones in inducing attacks in asymptomatic male mice. These studies have the potential to provide a novel animal model with a reliable and robust neurological phenotype in which to dissect biological mechanisms in a class of human neurological diseases where sex differences have been well established. PUBLIC HEALTH RELEVANCE Gender influences the clinical manifestations of many human diseases. Gender may affect prevalence, severity, or even specific clinical manifestations. The proposed studies are devoted to the development of a novel monogenic mouse model for elucidating the contributions of sex steroid hormones to the differences seen in so many human neurological diseases.